Download Life and death of transcriptional co

REVIEW
REVIEW
Epigenetics 6:8, 957-961; August, 2011; © 2011 Landes Bioscience
Life and death
of transcriptional co-activator p300
Jihong Chen and Qiao Li*
Department of Pathology and Laboratory Medicine; Faculty of Medicine; University of Ottawa; Ottawa, ON Canada
Key words: gene regulation, transcription factor, acetylation, phosphorylation, proteasome, ubiquitin, sumoylation, aggresome
Transcriptional co-activator p300, which contains an intrinsic
histone acetyltransferase activity, is required for an array of
important cellular processes. Tight control of p300 function
is critical to ensure precise histone acetylation and gene
activation. Dysregulation of p300 has been implicated in many
types of diseases and numerous studies have examined the
functional requirement of p300 to act as a co-activator or as
an acetyltransferase for other transcription regulators. Few,
however, have tackled how p300 itself is regulated and if posttranslational modification and spatial distribution are means of
p300 regulation. In this article, we present a current view on
the molecular mechanisms by which the activity and stability
of p300 is regulated.
Detailed kinetic studies with multiple molecular approaches have
later determined that p300 autoacetylation is predominantly
achieved in an intermolecular manner.24,25 To date, a total of 17
different autoacetylation sites have been identified in p300 HAT
domain,11,24,25 four of which have been validated in the endogenous p300 by mass spectrometry in a proteomics survey.26
Careful kinetic analyses have also provided significant insights
into the molecular mechanisms by which the HAT activity of
p300 is regulated. Many of the acetylated lysine residues are clustered in p300 HAT domain, which is sensitive to proteases, and
the catalytic activity of p300 is stimulated by autoacetylation of
some of these lysine residues.25 Autoacetylation of these lysine
residues appears to act as a reversible switch to control the HAT
activity and, consequently, the potential of p300 to act as a transcriptional co-activator.27-29 However, p300 harbors hundreds of
lysine residues and about half of them are located in functional
domains other than HAT. The extent of autoacetylation of the
full length p300 and the influence of the cellular milieau are not
known. In addition, it is still unclear if other cellular acetyltransferases can also acetylate p300 and play a role in the regulation of
the catalytic activity of p300.
©201
1L
andesBi
os
c
i
enc
e.
Donotdi
s
t
r
i
but
e.
Introduction
Transcriptional co-activator p300 was first identified as an E1A
binding protein due to its involvement in E1A function, particularly during cell cycle progression and cellular differentiation.1-3
It serves not only as a histone acetyltransferase (HAT), but also
as a factor acetyltransferase (FAT) for many transcription regulators through a hit-and-run mechanism.4-11 Besides having an
acetyltransferase domain, p300 also contains several conserved
functional domains through which it interacts with other cellular proteins (Fig. 1).12-15 Thus, the basic functional mode of
p300 is to serve as a HAT or a FAT, and to act as a scaffold
or bridge for transcription factors and other components of the
basal transcription machinery to facilitate chromatin remodeling
and to activate gene transcription (Fig. 2).16,17 Transcriptional coactivator CBP, which was initially identified as a CREB binding
protein and later found to be also an acetyltransferase,18-22 may be
regulated similarly to p300 given their structural and functional
similarities.
Regulation of p300 by Acetylation
The list of proteins that can be acetylated by p300 is long and
includes p300 itself. The autoacetylation of p300 was first
observed in acetylation assays using purified cell free systems.4,5,23
*Correspondence to: Qiao Li; Email: [email protected]
Submitted: 04/14/11; Accepted: 05/23/11
DOI: 10.4161/epi.6.8.16065
Regulation of p300 by Phosphorylation
Phosphorylation of p300 occurs abundantly during cell proliferation and differentiation.30-33 Cyclin-dependent kinases are
directly or indirectly involved in the regulation of p300 and CBP
during cell cycle progression.34-36 Site specific serine-threonine
phosphorylation have been identified in p300 and coupled to the
potential of p300 to act as a transcriptional co-activator in modulating target gene expression.32,37-41 In addition, p300 phosphorylation is also functionally linked to DNA damage response.42
Akt/protein kinase B (PKB) is a critical factor of cell proliferation and survival, and the function of Akt is mediated
through substrate phosphorylation at a consensus motif.43,44
Transcriptional co-activator p300, which contains such an optimal motif at the C-terminal region, interacts with Akt and is a
bona fide substrate for phosphorylation by Akt at this optimal
motif.45-49 The phosphorylation of p300 by Akt augments p300
HAT activity and induces the recruitment of p300 to its target
promoters, leading to histone acetylation and transcriptional
activation.48,49 More importantly, Akt also contributes to p300
transcriptional activity by increasing the metabolic stability of
p300, or maintaining the critical concentration of endogenous
www.landesbioscience.comEpigenetics
957
Figure 1. Listed are the examples of transcription factors, activators and co-activators associated with different functional domains of transcriptional
co-activator p300. Indicated are the cysteine and histidine motif (C/H), the CREB-binding domain (KIX), the bromodomain (Bromo) and the histone
acetyltransferase domain (HAT).
©201
1L
andesBi
os
c
i
enc
e.
Donotdi
s
t
r
i
but
e.
Figure 2. Transcriptional co-activator p300 regulates gene transcription
by acting as: (A) a histone acetyltransferase (HAT); (B) a transcription
factor acetyltransferase (FAT); (C) a scaffold for different transcription
factors on chromatin; (D) a bridge to connect the transcription factors
and the basal transcriptional machinery to activate gene transcription.
p300 protein in different cell systems.47,50 Thus, Akt is also a critical regulator of p300 turnover.
Regulation of p300 by the Proteasome Pathway
Many transcriptional factors and activators are regulated by the
26S proteasome, which is one of the major proteolysis systems of
the cell and localizes to both the cytoplasmic and nuclear compartments. It contains a 20S core particle capped at both ends
by the 19S regulatory particles, which recognize the protein
958
targets.51,52 Prior to degradation, target proteins are generally
covalently conjugated with polyubiquitin through a series of enzymatic reactions involving the ubiquitin-activating E1 enzymes,
E2 conjugases and E3 (and in some cases E4) ligases.53,54
The protein level of transcriptional co-activator p300 is essential for normal cellular processes such as embryonic development
and cell proliferation.55 Dysregulation of p300 has been implicated in many types of diseases. Therefore, p300 needs to be
tightly regulated to maintain normal cellular processes. So far,
multiple signaling pathways have been identified in the regulation of p300 turnover. Ubiquitination of p300 is associated
with unphosphorylated form,56 and the conjugation of ubiquitin occurs at specific regions such as the bromodomain region.57
Moreover, p300 can be modified by sumoylation near the bromodomain, which correlates with transcriptional repression.58
Similar to p300, CBP is also degraded through the ubiquitinproteasome pathway and promyelocytic leukemia (PML) nuclear
bodies appear to be the nuclear sites involved in ubiquitin-dependent degradation of CBP.59
Reversible phosphorylation can selectively signal protein degradation through the 26S proteasome pathway. For example,
MAP kinase p38 associates with p300, phosphorylates p300 and
induces proteasome-mediated p300 degradation.60 Interestingly,
Ras signaling pathway has also been implicated in selective p300
turnover.61 Nevertheless, phosphorylation of p300 by protein
kinases can also play an important role in maintaining the metabolic stability of this co-activator, such as in the case of Akt
(Fig. 3).47,50 Consequently, dephosphorylation of p300 by phosphatase can serve as a signal to designate the co-activator for
proteolysis. For example, the B56γ3 (PPP2R5C) regulatory subunit of protein phosphatase 2A (PP2A) is a negative regulator
Epigenetics
Volume 6 Issue 8
of p300 activity by targeting p300 degradation through the 26S proteasome pathway
(Fig. 3).62 Many small molecules have been
shown to induce p300 degradation through
the activation of different signaling transduction cascades leading to reversible phosphorylation of p300, and p300 activity is
dynamically regulated by these signaling
pathways.33,50,62-64
Regulation of p300
by Cellular Distribution
Tight regulation of nuclear p300 activity is
critical to ensure precisely controlled histone acetylation and transcriptional activation. Nucleo-cytoplasmic shuttling has been
implicated in the control of the availability
Figure 3. Nuclear Akt is important for maintaining p300 stability, suggesting a role for Akt in
and activity of this co-activator. In response
the regulation of gene transcription through the control of p300 activity. There is also a functo cellular stimuli, p300 distributes to the
tional interaction between p300 and the B56 regulatory subunit of PP2A, which targets p300
cytoplasm, which coincides with its ubiquitidegradation through the 26S proteasome in the nucleus. Additionally, p300 is a substrate of
the cytoplasmic-ubiquitin proteasome pathway.
nation and subsequent degradation (Fig. 3).57
The spatial control of p300, removing it
from the site of nuclear action, may be an
integral mechanism to regulate the function of the co-activator in separates its activity as ubiquitin ligase in the cytoplasm from as
response to cellular challenge, limiting its opportunity to inter- acetyltransferase required for p53-mediated gene transcription in
act with sequence-specific transcription factors, to acetylate his- the nucleus, which resolves effectively the opposite function of
tones or transcription factors, and to coordinate transcriptional p300 on p53 with respect to proteolysis and activation.
activation.
Aggresome can be formed as a consequence of overwhelmed
Perspectives
proteasome system in response to toxic proteins.65 The formation of aggresome is a cellular protective mechanism to sequester Increasing evidence has provided functional implications of
cytoplasmic protein aggregates or to deliver them for disposal p300 modification and metabolic stability in epigenetic regulathrough the alternative autophagosome pathway. Many nuclear tion, and shed molecular insights into the roles of cellular trafproteins including p300 are substrate of aggresome and undergo ficking and spatial distribution in gene transcription through
cytoplasmic degradation, which is an integral part of the normal p300 regulation. Activation of gene expression requires concellular regulatory process.57 Interestingly, p300 is differentially certed action of sequence-specific transcription factors, co-actirecruited to aggresome in breast cancer and in normal cells.66 vators and the transcription machinery at target enhancers and
Moreover, p300 localizes in the cytoplasm of oocytes within pri- promoters. Direct competition for a limited amount of p300
mordial follicles and distributes to the nucleus during different in a particular cellular environment or rapid removal of p300
stages of oocyte growth.67
from a specific chromatin locus is essential to synchronize the
Besides being degraded through the aggresome system, p300 activation or repression of gene sets, which often share overlapalso appears to play a functional role in the cytoplasm. Particularly, ping binding sites or require the function of p300 as an integrait contains a cytoplasmic E4 ubiquitin ligase activity.68-70 Thus, tor. The key determinants or specificities are not just residing
p300 is able to regulate p53 through multiple molecular path- in the transcription regulators, which recruit p300 to the loci,
ways. It not only acetylates p53 and acts as its transcriptional co- but also in the regulation of p300 by the cellular milieu per se.
activator, but also contributes to p53 ubiquitination through the Deciphering the molecular basis for the regulation of p300 by
intrinsic E3/E4 activities.68-70 The function of p300 is required post-translational modifications and spatial distribution will
for endogenous p53 polyubiquitination and rapid turnover. help us understand how p300 responds to signaling cascades and
Moreover, the intrinsic E4 ligase activity of p300 is exclusively exerts its diverse functions.
localized to the cytoplasm.68 This compartmentalization of p300
©201
1L
andesBi
os
c
i
enc
e.
Donotdi
s
t
r
i
but
e.
www.landesbioscience.comEpigenetics
959
References
1. Eckner R, Ewen ME, Newsome D, Gerdes M,
DeCaprio JA, Lawrence JB, et al. Molecular cloning and functional analysis of the adenovirus E1Aassociated 300-kD protein (p300) reveals a protein
with properties of a transcriptional adaptor. Genes Dev
1994; 8:869-84.
2. Stein RW, Corrigan M, Yaciuk P, Whelan J, Moran E.
Analysis of E1A-mediated growth regulation functions:
binding of the 300-kilodalton cellular product correlates with E1A enhancer repression function and DNA
synthesis-inducing activity. J Virol 1990; 64:4421-7.
3. Whyte P, Williamson NM, Harlow E. Cellular targets
for transformation by the adenovirus E1A proteins.
Cell 1989; 56:67-75.
4. Ogryzko VV, Schiltz RL, Russanova V, Howard BH,
Nakatani Y. The transcriptional coactivators p300 and
CBP are histone acetyltransferases. Cell 1996; 87:953-9.
5. Li Q, Herrler M, Landsberger N, Kaludov N, Ogryzko
VV, Nakatani Y, et al. Xenopus NF-Y pre-sets chromatin to potentiate p300 and acetylation-responsive
transcription from the Xenopus hsp70 promoter in
vivo. EMBO J 1998; 17:6300-15.
6. Li Q, Imhof A, Collingwood TN, Urnov FD, Wolffe
AP. p300 stimulates transcription instigated by ligandbound thyroid hormone receptor at a step subsequent
to chromatin disruption. EMBO J 1999; 18:5634-52.
7. Gu W, Roeder RG. Activation of p53 sequence-specific
DNA binding by acetylation of the p53 C-terminal
domain. Cell 1997; 90:595-606.
8. Boyes J, Byfield P, Nakatani Y, Ogryzko V. Regulation
of activity of the transcription factor GATA-1 by acetylation. Nature 1998; 396:594-8.
9. Soutoglou E, Katrakili N, Talianidis I. Acetylation
regulates transcription factor activity at multiple levels.
Mol Cell 2000; 5:745-51.
10. Liu X, Wang L, Zhao K, Thompson PR, Hwang Y,
Marmorstein R, et al. The structural basis of protein
acetylation by the p300/CBP transcriptional coactivator. Nature 2008; 451:846-50.
11. Karukurichi KR, Wang L, Uzasci L, Manlandro CM,
Wang Q, Cole PA. Analysis of p300/CBP histone acetyltransferase regulation using circular permutation and
semisynthesis. J Am Chem Soc 2011; 132:1222-3.
12. Chen J, Ghazawi FM, Li Q. Interplay of bromodomain and histone acetylation in the regulation of
p300-dependent genes. Epigenetics 2010; 5:509-15.
13. Kasper LH, Boussouar F, Ney PA, Jackson CW, Rehg J,
van Deursen JM, et al. A transcription-factor-binding
surface of coactivator p300 is required for haematopoiesis. Nature 2002; 419:738-43.
14. Kasper LH, Fukuyama T, Biesen MA, Boussouar F,
Tong C, de Pauw A, et al. Conditional knockout mice
reveal distinct functions for the global transcriptional
coactivators CBP and p300 in T-cell development. Mol
Cell Biol 2006; 26:789-809.
15. Bedford DC, Kasper LH, Fukuyama T, Brindle PK.
Target gene context influences the transcriptional
requirement for the KAT3 family of CBP and p300
histone acetyltransferases. Epigenetics 2010; 5:9-15.
16. Li Q, Sachs L, Shi YB, Wolffe AP. Modification
of Chromatin Structure by the Thyroid Hormone
Receptor. Trends Endocrinol Metab 1999; 10:157-64.
17. Goodman RH, Smolik S. CBP/p300 in cell growth,
transformation and development. Genes Dev 2000;
14:1553-77.
18. Chrivia JC, Kwok RP, Lamb N, Hagiwara M,
Montminy MR, Goodman RH. Phosphorylated CREB
binds specifically to the nuclear protein CBP. Nature
1993; 365:855-9.
19. Arias J, Alberts AS, Brindle P, Claret FX, Smeal T,
Karin M, et al. Activation of cAMP and mitogen
responsive genes relies on a common nuclear factor.
Nature 1994; 370:226-9.
20. Kwok RP, Lundblad JR, Chrivia JC, Richards JP,
Bachinger HP, Brennan RG, et al. Nuclear protein
CBP is a coactivator for the transcription factor CREB.
Nature 1994; 370:223-6.
21. Bannister AJ, Kouzarides T. The CBP co-activator is a
histone acetyltransferase. Nature 1996; 384:641-3.
22. Lundblad JR, Kwok RP, Laurance ME, Harter ML,
Goodman RH. Adenoviral E1A-associated protein
p300 as a functional homologue of the transcriptional
co-activator CBP. Nature 1995; 374:85-8.
23. Hamamori Y, Sartorelli V, Ogryzko V, Puri PL, Wu
HY, Wang JY, et al. Regulation of histone acetyltransferases p300 and PCAF by the bHLH protein twist and
adenoviral oncoprotein E1A. Cell 1999; 96:405-13.
24. Karanam B, Jiang L, Wang L, Kelleher NL, Cole PA.
Kinetic and mass spectrometric analysis of p300 histone acetyltransferase domain autoacetylation. J Biol
Chem 2006; 281:40292-301.
25. Thompson PR, Wang D, Wang L, Fulco M, Pediconi
N, Zhang D, et al. Regulation of the p300 HAT
domain via a novel activation loop. Nat Struct Mol Biol
2004; 11:308-15.
26. Kim SC, Sprung R, Chen Y, Xu Y, Ball H, Pei J, et
al. Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. Mol Cell 2006;
23:607-18.
27. Stiehl DP, Fath DM, Liang D, Jiang Y, Sang N. Histone
deacetylase inhibitors synergize p300 autoacetylation
that regulates its transactivation activity and complex
formation. Cancer Res 2007; 67:2256-64.
28. Hansson ML, Popko-Scibor AE, Saint Just Ribeiro
M, Dancy BM, Lindberg MJ, Cole PA, et al. The
transcriptional coactivator MAML1 regulates p300
autoacetylation and HAT activity. Nucleic Acids Res
2009; 37:2996-3006.
29. Karanam B, Wang L, Wang D, Liu X, Marmorstein
R, Cotter R, et al. Multiple roles for acetylation in the
interaction of p300 HAT with ATF-2. Biochemistry
2007; 46:8207-16.
30. Yaciuk P, Moran E. Analysis with specific polyclonal
antiserum indicates that the E1A-associated 300-kDa
product is a stable nuclear phosphoprotein that undergoes cell cycle phase-specific modification. Mol Cell
Biol 1991; 11:5389-97.
31. Kitabayashi I, Eckner R, Arany Z, Chiu R, Gachelin G,
Livingston DM, et al. Phosphorylation of the adenovirus E1A-associated 300 kDa protein in response to
retinoic acid and E1A during the differentiation of F9
cells. EMBO J 1995; 14:3496-509.
32. Schwartz C, Beck K, Mink S, Schmolke M, Budde B,
Wenning D, et al. Recruitment of p300 by C/EBPbeta
triggers phosphorylation of p300 and modulates coactivator activity. EMBO J 2003; 22:882-92.
33. Brouillard F, Cremisi CE. Concomitant increase of histone acetyltransferase activity and degradation of p300
during retinoic acid-induced differentiation of F9 cells.
J Biol Chem 2003; 278:39509-16.
34. Perkins ND, Felzien LK, Betts JC, Leung K, Beach
DH, Nabel GJ. Regulation of NFkappaB by cyclindependent kinases associated with the p300 coactivator.
Science 1997; 275:523-7.
35. Felzien LK, Farrell S, Betts JC, Mosavin R, Nabel GJ.
Specificity of cyclin E-Cdk2, TFIIB and E1A interactions with a common domain of the p300 coactivator.
Mol Cell Biol 1999; 19:4241-6.
36. Ait-Si-Ali S, Ramirez S, Barre FX, Dkhissi F, MagnaghiJaulin L, Girault JA, et al. Histone acetyltransferase
activity of CBP is controlled by cycle-dependent
kinases and oncoprotein E1A. Nature 1998; 396:
184-6.
37. Yuan LW, Gambee JE. Phosphorylation of p300 at
serine 89 by protein kinase C. J Biol Chem 2000;
275:40946-51.
38. Gusterson R, Brar B, Faulkes D, Giordano A, Chrivia
J, Latchman D. The transcriptional co-activators CBP
and p300 are activated via phenylephrine through
the p42/p44 MAPK cascade. J Biol Chem 2002;
277:2517-24.
39. See RH, Calvo D, Shi Y, Kawa H, Luke MP, Yuan Z.
Stimulation of p300-mediated transcription by the
kinase MEKK1. J Biol Chem 2001; 276:16310-7.
40. Chen YJ, Wang YN, Chang WC. ERK2-mediated
C-terminal serine phosphorylation of p300 is vital
to the regulation of epidermal growth factor-induced
keratin 16 gene expression. J Biol Chem 2007;
282:27215-28.
41. Bratton MR, Frigo DE, Vigh-Conrad KA, Fan D,
Wadsworth S, McLachlan JA, et al. Organochlorinemediated potentiation of the general coactivator
p300 through p38 mitogen-activated protein kinase.
Carcinogenesis 2009; 30:106-13.
42. Jang ER, Choi JD, Jeong G, Lee JS. Phosphorylation of
p300 by ATM controls the stability of NBS1. Biochem
Biophys Res Commun 2010; 397:637-43.
43. Alessi DR, Caudwell FB, Andjelkovic M, Hemmings
BA, Cohen P. Molecular basis for the substrate specificity
of protein kinase B; comparison with MAPKAP kinase-1
and p70 S6 kinase. FEBS Lett 1996; 399:333-8.
44. Obata T, Yaffe MB, Leparc GG, Piro ET, Maegawa H,
Kashiwagi A, et al. Peptide and protein library screening defines optimal substrate motifs for AKT/PKB.
J Biol Chem 2000; 275:36108-15.
45. Guo S, Cichy SB, He X, Yang Q, Ragland M, Ghosh
AK, et al. Insulin suppresses transactivation by CAAT/
enhancer-binding proteins beta (C/EBPbeta). Signaling
to p300/CREB-binding protein by protein kinase B
disrupts interaction with the major activation domain
of C/EBPbeta. J Biol Chem 2001; 276:8516-23.
46. Mayo MW, Denlinger CE, Broad RM, Yeung F,
Reilly ET, Shi Y, et al. Ineffectiveness of Histone
Deacetylase Inhibitors to Induce Apoptosis Involves the
Transcriptional Activation of NF{kappa}B through the
Akt Pathway. J Biol Chem 2003; 278:18980-9.
47. Chen J, Halappanavar SS, St-Germain JR, Tsang BK,
Li Q. Role of Akt/protein kinase B in the activity of
transcriptional coactivator p300. Cell Mol Life Sci
2004; 61:1675-83.
48. Huang WC, Chen CC. Akt phosphorylation of p300 at
Ser-1834 is essential for its histone acetyltransferase and
transcriptional activity. Mol Cell Biol 2005; 25:6592-602.
49. Liu Y, Denlinger CE, Rundall BK, Smith PW, Jones
DR. Suberoylanilide hydroxamic acid induces Aktmediated phosphorylation of p300, which promotes
acetylation and transcriptional activation of RelA/p65.
J Biol Chem 2006; 281:31359-68.
50. Ji M, Zhang Q, Ye J, Wang X, Yang W, Zhu D.
Myostatin induces p300 degradation to silence cyclin
D1 expression through the PI3K/PTEN/Akt pathway.
Cell Signal 2008; 20:1452-8.
51. Lee DH, Goldberg AL. Proteasome inhibitors: valuable
new tools for cell biologists. Trends Cell Biol 1998;
8:397-403.
52. Ciechanover A. Proteolysis: from the lysosome to ubiquitin and the proteasome. Nat Rev Mol Cell Biol 2005;
6:79-87.
53. Hershko A, Ciechanover A. The ubiquitin system.
Annu Rev Biochem 1998; 67:425-79.
54. Ciechanover A. The ubiquitin-proteasome pathway: on
protein death and cell life. EMBO J 1998; 17:7151-60.
55. Yao TP, Oh SP, Fuchs M, Zhou ND, Ch’ng LE,
Newsome D, et al. Gene dosage-dependent embryonic
development and proliferation defects in mice lacking the
transcriptional integrator p300. Cell 1998; 93:361-72.
56.Avantaggiati ML, Carbone M, Graessmann A,
Nakatani Y, Howard B, Levine AS. The SV40 large T
antigen and adenovirus E1a oncoproteins interact with
distinct isoforms of the transcriptional co-activator,
p300. EMBO J 1996; 15:2236-48.
57. Chen J, Halappanavar S, Th’ ng JP, Li Q. Ubiquitindependent distribution of the transcriptional coactivator p300 in cytoplasmic inclusion bodies. Epigenetics
2007; 2:92-9.
58. Girdwood D, Bumpass D, Vaughan OA, Thain A,
Anderson LA, Snowden AW, et al. p300 Transcriptional
Repression Is Mediated by SUMO Modification. Mol
Cell 2003; 11:1043-54.
©201
1L
andesBi
os
c
i
enc
e.
Donotdi
s
t
r
i
but
e.
960
Epigenetics
Volume 6 Issue 8
59. St-Germain JR, Chen J, Li Q. Involvement of PML
nuclear bodies in CBP degradation through the ubiquitin-proteasome pathway. Epigenetics 2008; 3:342-9.
60. Poizat C, Puri PL, Bai Y, Kedes L. Phosphorylationdependent degradation of p300 by doxorubicin-activated p38 mitogen-activated protein kinase in cardiac
cells. Mol Cell Biol 2005; 25:2673-87.
61. Sanchez-Molina S, Oliva JL, Garcia-Vargas S, Valls E,
Rojas JM, Martinez-Balbas MA. The histone acetyltransferases CBP/p300 are degraded in NIH 3T3 cells
by activation of Ras signalling pathway. Biochem J
2006; 398:215-24.
62. Chen J, St-Germain JR, Li Q. B56 regulatory subunit of protein phosphatase 2A mediates valproic
acid-induced p300 degradation. Mol Cell Biol 2005;
25:525-32.
63. Li Q, Su A, Chen J, Lefebvre YA, Hache RJ.
Attenuation of glucocorticoid signaling through targeted degradation of p300 via the 26S proteasome
pathway. Mol Endocrinol 2002; 16:2819-27.
64. Poizat C, Sartorelli V, Chung G, Kloner RA, Kedes
L. Proteasome-mediated degradation of the coactivator p300 impairs cardiac transcription. Mol Cell Biol
2000; 20:8643-54.
65. Johnston JA, Ward CL, Kopito RR. Aggresomes: a cellular response to misfolded proteins. J Cell Biol 1998;
143:1883-98.
66. Fermento ME, Gandini NA, Lang CA, Perez JE,
Maturi HV, Curino AC, et al. Intracellular distribution
of p300 and its differential recruitment to aggresomes
in breast cancer. Exp Mol Pathol 2010; 88:256-64.
67. Kwok RP, Liu XT, Smith GD. Distribution of co-activators CBP and p300 during mouse oocyte and embryo
development. Mol Reprod Dev 2006; 73:885-94.
68. Shi D, Pop MS, Kulikov R, Love IM, Kung AL,
Grossman SR. CBP and p300 are cytoplasmic E4
polyubiquitin ligases for p53. Proc Natl Acad Sci USA
2009; 106:16275-80.
69. Grossman SR, Deato ME, Brignone C, Chan HM,
Kung AL, Tagami H, et al. Polyubiquitination of p53
by a ubiquitin ligase activity of p300. Science 2003;
300:342-4.
70. Grossman SR, Perez M, Kung AL, Joseph M, Mansur
C, Xiao ZX, et al. p300/MDM2 complexes participate
in MDM2-mediated p53 degradation. Mol Cell 1998;
2:405-15.
©201
1L
andesBi
os
c
i
enc
e.
Donotdi
s
t
r
i
but
e.
www.landesbioscience.comEpigenetics
961